The overall goal of this Program Project Grant application is to define the initiating molecular events giving rise to vascular lesion formation in atherosclerosis and following mechanical vascular injury. We shall investigate three interrelated processes leading to vascular lesion formation: a) oxidative stress and its effects on the endothelium (Projects 1-2); b) thrombin deposition and its effects in mediating vascular lesion formation after denuding vascular injury (Projects 2, 3 and 4); and c) growth factor production and secretion by vascular wall cells and platelets in response to injury and during atherogenesis (Projects 3 and 4). More specifically, in Project 1, we shall examine the regulation of superoxide dismutase(s) and nitric oxide synthase gene and protein expression in endothelial cells exposed to oxidative stress. A central thesis is that there is inadequate compensatory regulation of reactive oxygen intermediate scavenging pathways in atherosclerosis. Project 2 will test the hypothesis that oxidative/metabolic stress represents a linkage between hyperlipidemia and stimulated monocyte adhesion in the endothelium. Project 3 will explore the molecular mechanisms of thrombin receptor expression, regulation and function in platelets, endothelial cells and vascular smooth muscle cells. Project 4 will elucidate, in a primate model of vascular injury, the relative roles of thrombin, platelets and growth factors in intimal proliferation. We propose to examine each of these putative mechanisms by studying the regulation of molecular events in vitro, inducing and preventing (through the use of implanted drug delivery devices) vascular lesion formation in experimental animals, and evaluating the applicability of the experimentally derived hypotheses to human vascular disease through the Morphology/Clinical Research Core and through the clinical studies on the effects of atherogenic lipid fractions on endothelial metabolism in Project 2. This Program Project Grant application represents a multidisciplinary collaboration among scientists with established expertise who are committed to understanding and developing new therapeutic approaches to human vascular disease.